Comparison of the antinociceptive effect of morphine, methadone, buprenorphine and codeine in two substrains of Sprague-Dawley rats.

Sprague-Dawley rats from two different vendors, Möllegård, Denmark and B&K Universal, Sweden, have been tested for the antinociceptive effect of morphine, methadone, buprenorphine and codeine on the hot plate. Morphine and methadone had significantly weaker effect in Möllegård rats compare to B&K rats. In contrast, the effect of buprenorphine was stronger in Möllegård rats than in B&K rats and the effect of codeine was similar in the two substrains. Plasma levels of morphine, morphine-6-glucuronide, morphine-3-glucuronide, buprenorphine and norbuprenorphine were determined at two time points after drug injection. Möllegård rats had significantly lower mean plasma level of morphine and significantly higher ratio of morphine-3-glucuronide/morphine at 30 min, compared to B&K rats. No difference was seen for the metabolism of buprenorphine in the two substrains. The results suggest that Möllegård rats metabolize morphine to morphine-3-glucuronide to a greater extent than B&K rats, and this may at least partly underlie the substrain difference in the effect of morphine. It is also suggested that the antinociceptive mechanisms of buprenorphne may be different from those of morphine and methadone.

Comparison of response characteristics of cutaneous mechanoreceptors in normal and neuropathic Sprague-Dawley and spontaneously hypertensive rats.

The activity of single myelinated afferents was recorded from dorsal roots L4-5 in normal Spontaneously Hypertensive rats (SHR) and animals that developed mechanical hypersensitivity following ischemic injury to the sciatic nerve. Control and neuropathic SHRs had significantly higher paw withdrawal threshold to mechanical stimulation than control and neuropathic Sprague-Dawleys (SD). In the SHR rats the mechanical response properties of afferents conducting through the injury site were similar to normals and many of the afferents not conducting through the injury site had spontaneous activity. The only significant difference between the two strains was a faster conduction velocity in afferents recorded from SHR than SD rats. Thus, the behavioral hyposensitivity and less development of mechanical allodynia of SHR rats, compared to SD is not due to differences in the properties of myelinated afferents, but probably involves differences in central inhibitory mechanisms in the two strains.

Differential antinociception by morphine and methadone in two sub-strains of Sprague-Dawley rats and its potentiation by dextromethorphan.

The antinociceptive effect of morphine and methadone was tested in two substrains of Sprague-Dawley (SD) rats, from B&K Universal, Sweden (BK) and Mollegård, Denmark (DK). In both sub-strains of SD rats subcutaneous morphine or methadone produced dose-dependent antinociception on the hot plate test. However, the effect of the opioids was less in DK-SD than BK-SD rats, particularly for morphine as it failed to produce maximal antinociception even at high doses. Dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, potentiated the antinociceptive effect of morphine and methadone in the DK-SD rats. The potentiation of morphine by dextromethorphan was significantly greater than its effect on methadone at equipotent doses. The results showed that there is a sub-strain difference for SD rats in the response to the antinociceptive effect of opioids, which may be due to greater NMDA receptor activity in DK-SD than in BK-SD rats. The higher efficacy of methadone may be derived from its proposed NMDA receptor blocking property and/or high intrinsic activity.

Response characteristics of cutaneous mechanoreceptors in neuropathic rats.

The activity of single myelinated afferents was recorded from dorsal roots L4-5 in normal Sprague-Dawley rats and animals that developed mechanical hypersensitivity following ischemic injury to the sciatic nerve. The mechanical response properties and conduction velocity of afferents conducting through the injury site (about 50% of units) were similar to controls. However, the majority of afferents not conducting through the injury site exhibited ongoing activity. The results suggest that mechanical allodynia may be at least partly due to the central integration of activity arising from these two populations of afferents in neuropathic rats.

Reduced tolerance to the anti-hyperalgesic effect of methadone in comparison to morphine in a rat model of mononeuropathy.

The development of tolerance to chronically administered methadone and morphine was examined in a rat model of neuropathic pain after ischemic nerve injury. In drug naive neuropathic rats systemically administered morphine or methadone similarly and dose-dependently alleviated mechanical allodynia. Tolerance to the anti-hyperalgesic effect of equally effective doses of morphine (10mg/kg) or methadone (5mg/kg) developed upon administration twice daily. However, the rate of tolerance development was significantly slower for methadone in comparison to morphine. Chronic morphine treatment for 14 days induced almost complete loss of the anti-allodynic effect to morphine, whereas methadone still had partial effect after 21 days of chronic treatment. Partial cross-tolerance was observed between morphine and methadone. It is suggested that the delayed development of tolerance to methadone in neuropathic rats may be related to the higher intrinsic activity of methadone compared to morphine, as well as the N-methyl-D-aspartate receptor blocking property of methadone. The latter may also contribute to preservation of mu-opioid anti-nociception following chronic methadone treatment.